The Journal of Organic Chemistry
NOTE
N,N-diethylchloroformamide (7.5 mL, 58.9 mmol) in CH3CN (100 mL,
ACS grade for direct use) was heated to reflux for 2 h. Upon cooling, the
resulting mixture was filtered and washed by ethyl acetate
(3 ꢁ 100 mL). The filtrate was concentrated in vacuo to give the
residue, which was directly subjected to flash column chromatography
(EtOAcꢀhexanes, 1:4) to afford O-(2-iodophenyl)-N,N-diethylcarba-
mate as an amber oil (14.8 g, 95% yield). 1H NMR (400 MHz, CDCl3) δ
7.79 (1H, d, J = 8 Hz), 7.31ꢀ7.35 (1H, m), 7.17 (1H, d, J = 8 Hz), 6.92
(1H, t, J = 7.6 Hz), 3.52 (2H, q, J = 6.8 Hz), 3.39 (2H, q, J = 6.8 Hz), 1.32
(3H, t, J = 6.8 Hz), 1.22 (3H, t, J = 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 153.0, 151.7, 139.1, 129.1, 126.8, 123.3, 121.7, 90.8, 42.3, 42.0,
14.3, 13.3.
amber oil (173 mg, 76% yield). IR (film) 2975, 2937, 2901, 2877, 1720,
1683, 1640, 1606, 1579, 1523, 1484, 1432, 1348, 1361, 1314, 1279, 1246,
1
1224, 1106, 1066, 912, 881, 844, 759, 633 cmꢀ1; H NMR (400 MHz,
CDCl3) δ 7.69 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz), 6.97 (1H, s),
3.70 (2H, s), 3.12 (2H, q, J = 7.1 Hz), 3.03 (2H, s), 1.38 (3H, t, J = 7.1 Hz),
1.23 (3H, t, J = 7.2 Hz), 0.98 (3H, t, J = 7.1 Hz), 0.32 (9H, s); 13C NMR
(100 MHz, CDCl3) δ 201.3, 168.1, 166.8, 131.9, 131.0, 123.3, 122.0,
120.4, 115.7, 43.0, 38.9, 33.4, 13.4, 12.5, 8.3, ꢀ2.0; HRMS (FABþ) calcd
for C19H27NO3Si [(M þ H)þ] 346.1838, found 346.1839.
(þ)-(R)-2-Trimethylsilylconcentricolide (8): To a solution of
N,N-diethyl-6-propionyl-2-trimethylsilylbenzofuran-7-carboxamide (7)
(104 mg, 0.30 mmol) and (S)-B-nBu-CBS catalyst19 (0.15 mmol) at 0 °C
with vigorous stirring was added BH3ꢀTHF (1.0 M in THF, 0.45 mL,
0.45 mmol) slowly along the side wall of the reaction flask by a syringe
pump over 5 h. After completion of the addition and another 1 h of
stirring at 0 °C, KOAc (294 mg, 3.0 mmol) and o-xylene (2 mL) were
added to the flask followed by the removal of THF under reduced
pressure. The resulting mixture was directly heated at 140 °C for 1 h.
Upon cooling, water (10 mL) was added and a bilayer solution was then
extracted with EtOAc (3 ꢁ 10 mL). The combined extracts were washed
with brine (5 mL), dried over MgSO4, concentrated, and column
chromatographied (EtOAcꢀhexanes, 1:19) to furnish 2-trimethylsilyl-
N,N-Diethyl-2-hydroxy-3-iodobenzamide (4):18 To a solu-
tion of diisopropylamine (169 μL, 1.20 mmol) in THF (1.2 mL) was
slowly added n-BuLi (2.42 M in n-hexanes, 0.50 mL, 1.21 mmol)
at ꢀ60 °C under nitrogen within 5 min. After the mixture was stirred
for 20 min at ꢀ60 °C, a solution of O-(2-iodophenyl)-N,N-diethylcar-
bamate (3) (319 mg, 1.0 mmol) in THF (1.2 mL) was added within
5 min. The reaction mixture was stirred at ꢀ60 °C for 30 min, then allowed
to warm to room temperature and stirred for another 2 h. The reaction
was quenched with saturated NH4Cl solution (10 mL). After removal of
the organic solvent, the aqueous layer was acidified with 1 N HCl to pH 3
and the resulting residue was extracted with EtOAc (3 ꢁ 30 mL). The
combined extract was washed with brine (10 mL), dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash column
chromatography (EtOAcꢀhexanes, 1:4) to afford N,N-diethyl-2-hydro-
xy-3-iodobenzamide as an amber oil (0.24 g, 72% yield). 1H NMR (400
MHz, CDCl3) δ 9.42 (1H, s), 7.73 (1H, d, J = 7.4 Hz), 7.22 (1H, d,
J = 7.3 Hz), 6.61 (1H, t, J = 7.3 Hz), 3.46 (4H, q, J = 6.7 Hz), 1.22 (6H, t,
J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 170.3, 156.8, 141.3, 127.4,
120.3, 118.8, 86.2, 42.1, 13.2.
concentricolide as a colorless oil (71 mg, 86% yield, 80% ee). [R]25
D
þ13.9 (c 0.92, CHCl3, 80% ee); IR (film) 2966, 2936, 1760, 1635, 1596,
1528, 1462, 1328, 1251, 1283, 1178, 1150, 1109, 1056, 955, 844, 792,
758, 685 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 7.85 (1H, d, J = 7.9 Hz),
7.21 (1H, d, J = 7.9 Hz), 7.05 (1H, s), 5.54 (1H, dd, J = 7.5, 4.5 Hz),
2.24ꢀ2.06 (1H, m), 1.91ꢀ1.78 (1H, m), 0.99 (1H, t, J = 7.3 Hz), 0.38
(9H, s); 13C NMR (125 MHz, CDCl3) δ 168.2, 166.2, 153.2, 147.9,
129.8, 127.5, 115.8, 115.4, 110.8, 82.6, 27.9, 8.7, ꢀ1.83; HRMS (EIþ) calcd
for C15H18O3Si (Mþ) 274.1025, found 274.1033; enantioselectivity was
determined by HPLC analysis (Chiralpak-AD, 1.0 mL/min, 220 nm,
hexanes/i-PrOH 99/1); retention times were 11.8 (enantiomer) and
13.1 min (major).
(þ)-(R)-Concentricolide (1): To a solution of 2-trimethylsilyl-
concentricolide (8) (63 mg, 0.23 mmol, 80% ee) and AcOH (14 μL,
0.23 mmol) in THF (2 mL) was added tetra-n-butylammonium fluoride
(TBAF, 1 M in THF, 0.25 mL, 0.25 mmol) at room temperature. Upon
completion of the conversion, the resulting solution was concentrated
and purified by flash column chromatography (EtOAcꢀhexanes, 1:9) to
afford concentricolide as a white solid (52 mg, 82% yield, 80% ee). Mp
89ꢀ90 °C (petroleum ether/acetone); mp 116ꢀ117 °C (ethyl acetate/
hexane) [lit. mp 89ꢀ90 °C, petroleum ether/acetone]; [R]25D þ26.1
(c 0.81, CH3OH); IR (film) 2970, 2933, 1761, 1640, 1595, 1536, 1435,
1321, 1204, 1109, 1061, 976, 837, 768, 665 cmꢀ1; 1H NMR (500 MHz,
CDCl3) δ 7.91 (1H, d, J = 8.0 Hz,), 7.80 (1H, d, J = 2.1 Hz), 7.27 (1H, d,
J = 8.0 Hz), 6.90 (1H, d, J = 2.1 Hz), 5.57 (1H, dd, J = 7.0, 4.2 Hz),
2.20ꢀ2.18 (1H, m), 1.86ꢀ1.83 (1H, m), 1.01 (3H, t, J = 7.4 Hz); 1H
NMR (500 MHz, CDOD3) δ 8.02 (1H, d, J = 8.0 Hz), 7.94 (1H, d,
J = 2.2 Hz), 7.41 (1H, d, J = 8.0 Hz), 7.03 (1H, d, J = 2.2 Hz), 5.66 (1H,
dd, J = 6.9, 4.1 Hz), 2.24ꢀ2.17 (1H, m), 1.88ꢀ1.80 (1H, m), 0.95 (3H, t,
J = 7.4 Hz); 13C NMR (125 MHz, CDCl3) δ 168.1, 149.8, 147.9, 146.6,
129.0, 127.9, 116.1, 111.1, 106.6, 82.9, 27.9, 8.8; 13C NMR (125 MHz,
CDOD3) δ 170.1, 151.0, 149.7, 148.1, 130.6, 129.6, 117.6, 111.6, 107.9,
84.7, 28.7, 8.9; HRMS (EIþ) calcd for C12H10O3 (Mþ) 202.0630,
found 202.0633; enantioselectivity was determined by HPLC analysis
(Chiralpak-AD, 1.0 mL/min, 220 nm, hexanes/i-PrOH 99/1); retention
times were 48.7 (major) and 55.4 min (enantiomer).
N,N-Diethyl-2-trimethylsilylbenzofuran-7-carboxamide (6): A
solution of N,N-diethyl-2-hydroxyl-3-iodobenzamide (280 mg, 0.88 mmol),
trimethylsilylacetylene (0.19 mL, 1.32 mmol), and Et3N (0.92 mL, 3.52
mmol) in CH3CN (1.76 mL) in a Schlenk tube was degassed by two
freezeꢀpumpꢀthaw cycles and charged with Pd(PPh3)2Cl2 (6.2 mg,
8.8 μmol) and CuI (1.2 mg, 11.6 μmol) under nitrogen. The resulting
mixture was stirred at 65 °C for 96 h. Upon completion of conversion
1
(monitored by H NMR), the solution was concentrated and directly
purified by flash column chromatography (EtOAcꢀhexanes, 1:9) to afford
N,N-diethyl-2-trimethylsilylbenzofuran-7-carboxamide as an amber oil (223
mg, 88% yield). IR (film) 2965, 2935, 2899, 1633, 1534, 1430, 1481, 1380,
1
1346, 1284, 1250, 1121, 1067, 910, 845, 752, 634 cmꢀ1; H NMR (400
MHz, CDCl3) δ7.57 (1H, dd, J= 7.7, 1.3 Hz,), 7.28 (1H, dd, J= 7.3, 1.3 Hz),
7.21 (1H, t, J=7.5Hz), 6.96(1H, s), 3.66(2H, q,J= 7.1 Hz), 3.20 (2H, q, J=
7.1 Hz), 1.31 (3H, t, J = 7.1 Hz), 1.05 (3H, t, J = 7.1 Hz), 0.32 (s, 8H); 13C
NMR (100 MHz, CDCl3) δ 167.5, 164.1, 153.2, 128.4, 122.9, 122.6, 121.8,
121.4, 116.0, 42.9, 38.9, 14.0, 12.8, ꢀ1.9; HRMS (FABþ) calcd for
C16H23NO2Si [(M þ H)þ] 290.1580, found 290.1576.
N,N-Diethyl-6-propionyl-2-trimethylsilylbenzofuran-7-
carboxamide (7): To a solution of N,N-diethyl-2-trimethylsilylben-
zofuran-7-carboxamide (6) (190 mg, 0.66 mmol) and tetramethylethy-
lenediamine (TMEDA) (156 μL, 1.05 mmol) in THF (2.2 mL)
at ꢀ80 °C was added slowly a solution of t-BuLi (1.44 M in pentane,
0.69 mL, 0.99 mmol). The color of the solution turned to deep-blue
gradually and reached a stable state while the lithiation reagent was
added. The resulting solution was kept at ꢀ80 °C for 1 h and the neat
N-methoxy-N-methylpropionamide (120 mg, 0.99 mmol) was added
slowly at the same temperature. After another 1 h of stirring at ꢀ80 °C,
the reaction was quenched with saturated NH4Cl solution (5 mL). THF
was removed and the residue was diluted with EtOAc (15 mL), washed with
1NHCl(2ꢁ 10 mL) and brine (10 mL), dried over MgSO4, concentrated,
and purified by column chromatography (EtOAcꢀhexanes, 1:4) to afford
N,N-diethyl-6-propionyl-2-trimethylsilylbenzofuran-7-carboxamide as an
(þ)-(R)-2-Bromoconcentricolide (9): To a solution of 2-tri-
methylsilylconcentricolide (8) (106 mg, 0.39 mmol, 80% ee) in CH2Cl2
(3 mL) was added slowly a solution of bromine in CH2Cl2 (0.6 M in
CH2Cl2, 1.3 mL, 0.78 mmol) at room temperature. After 10 min, the
reaction was treated with Et3N (0.2 mL) and concentrated to obtain the
crude product. The residue was purified by flash column chromatography
4156
dx.doi.org/10.1021/jo2004132 |J. Org. Chem. 2011, 76, 4154–4157